CN103201275A - Salt(s) of 7-cyclopentyl-2 -(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof - Google Patents
Salt(s) of 7-cyclopentyl-2 -(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof Download PDFInfo
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- 0 CCNc(cc1)ncc1N(CC1)CCN1*=O Chemical compound CCNc(cc1)ncc1N(CC1)CCN1*=O 0.000 description 3
- RMULRXHUNOVPEI-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1c(cc1)cnc1N)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1c(cc1)cnc1N)=O RMULRXHUNOVPEI-UHFFFAOYSA-N 0.000 description 1
- GROBKWQTIGHAKQ-UHFFFAOYSA-N Cc1ccc([N+](C)([O-])O)nc1 Chemical compound Cc1ccc([N+](C)([O-])O)nc1 GROBKWQTIGHAKQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
This invention relates to (1) process of making 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and salts thereof; (2) novel salt(s) of 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; (3) pharmaceutical compositions comprising the same; and (4) methods of treatment using the same.
Description
[technical field]
The present invention relates to: the method for (1) preparation 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide and salt thereof; (2) the novel salt of 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide; (3) comprise the pharmaceutical composition of described material; And (4) use the methods for the treatment of of described material.
[background technology]
7-cyclopentyl-the 2-of formula (I) (5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide
And synthetic the specific descriptions in WO2010/020675A1, among the embodiment 74.WO2010/020675 announcement formula (I) compound has valuable pharmacological property and for example can be used as: the inhibitor of (1) cyclin dependant kinase (particularly, being selected from the cell cycle protein dependent kinase of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9); And conditioning agent and/or the inhibitor of (2) liver starch synthase kinase-3 (GSK-3).
WO2010/020675 does not disclose or points out the succinate of 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide.
[summary of the invention]
The present invention relates to the succinate of 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide.This succinate has the structure of formula (II)
The invention still further relates to the method for a kind of preparation formula (II) compound.
The invention further relates to the method for a kind of preparation formula (I) compound.
The present invention further also relates to the method for a kind of preparation formula (III) compound:
The present invention further also relates to the method for a kind of preparation formula (IV) compound:
The invention further relates to pharmaceutical composition, this pharmaceutical composition contains salt and at least a pharmaceutically acceptable vehicle, thinner, carrier or the vehicle of formula (II).
The invention still further relates to a kind of cell cycle for the treatment of and regulate protein dependent kinase (particularly, be selected from the cyclin kinases of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9) inhibition have the method for the disease of reaction, this method comprises that formula (II) compound of will treatment going up significant quantity needs the step of the individuality of this treatment.
[Brief Description Of Drawings]
Dynamic steam absorption (DVS) isothermal curve figure (0-90-0% relative humidity (RH) circulation) of Fig. 1 display type (II) compound.
Fig. 2 is presented at the X-ray powder diffraction (XRPD) (0-90-0%RH circulation) behind the DVS of formula (II) compound.
Fig. 3 is presented at the poor formula scanning calorimetry (DVS) (0-90-0%RH circulation) of formula (II) compound behind the DVS.
Fig. 4 is presented at the thermogravimetic analysis (TGA) (TGA) (0-90-0%RH circulation) of formula (II) compound behind the DVS.
The DVS isothermal curve figure of Fig. 5 display type (II) compound (0-80-0%RH circulation).
XRPD behind the DVS of Fig. 6 display type (II) compound (0-80-0%RH circulation).
[detailed Description Of The Invention]
The present invention relates to the succinate of 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide.
This succinate has formula (II) structure:
The succinate of 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide can be the form of non-hydrate, hydrate or its mixture.
In one embodiment, this succinate is the form of non-hydrate greater than 99.9%.
In one embodiment, this succinate is the form of non-hydrate greater than 99%.
In one embodiment, this succinate is the form of non-hydrate greater than 97%.
In one embodiment, this succinate is the form of non-hydrate greater than 95%.
In one embodiment, this succinate is the form of non-hydrate greater than 90%.
The non-hydrate form of the succinate of 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide has satisfactory stability, non-hygroscopic and good solubility.
The invention still further relates to the method for a kind of preparation formula (I) compound and formula (II) compound:
The process flow sheet of preparation formula (I) compound and formula (II) compound
The present invention is further about the method for a kind of preparation formula (III) compound.
Compare the method for previous manufacturing formula (III) compound, the inventive method is increased to 30% with the overall productive rate of formula (III) compound (being A1) from 4%.In addition, this modification method does not need five required tubing string purification steps of previous method.
The present invention is also further about the method for preparation formula (IV) compound:
In formula of the present invention (IV) compound (being A2) is synthetic, develops and to use propyl carbinol the chlorine among the A2d to be substituted by the simple and easy method of A2c as solvent.This method can improve productive rate and omit carries out chromatography purification for further processing to formula (IV) compound.
In a word, the present invention develops in order to the scalable industrial scale of making initial substance A1 (formula (III) compound), A2 (formula (IV) compound), free alkali A4 (formula (I) compound) and succinate A6 (formula (II) compound), safer, simpler, productive rate is higher and cost benefit is higher method.Compare previous synthetic method, this overall craft shortens synthesis step and overall yield is promoted to 12% from 0.9%.
The present invention is further about pharmaceutical composition, and this pharmaceutical composition comprises salt and at least a pharmaceutically acceptable vehicle, thinner, carrier or the vehicle of formula (II).
The invention still further relates to a kind of cell cycle for the treatment of and regulate protein dependent kinase (particularly, be selected from the cyclin dependant kinase of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9) inhibition have the method for the disease of reaction, this method comprises that formula (II) compound of will treatment going up significant quantity needs the step of the individuality of this treatment.
The disease that the inhibition that described cell cycle is regulated protein dependent kinase has a reaction includes, but is not limited to breast cancer, urogenital cancer, lung cancer, gastrointestinal cancer, epidermoid carcinoma, melanoma, ovarian cancer, carcinoma of the pancreas, neuroblastoma, head and neck cancer or bladder cancer or kidney, brain or the cancer of the stomach on the broad sense more; Leukemia, hyperplasia, cancer of the stomach, colorectal carcinoma, laryngocarcinoma, lymphsystem cancer, genitourinary tract cancer, osteocarcinoma, prostate cancer, minicell type lung cancer, neurospongioma cancer, colorectal carcinoma, kidney, epithelial cancer, liver cancer, esophagus cancer, hemopoietic system cancer, lymphoma, myelomatosis, follicular carcinoma of thyroid; Between the tumour in matter source, for example fibrosarcoma or rhabdosarcoma; The tumour of maincenter or peripheral nervous system, for example astrocytoma, neuroblastoma, neurospongioma or schwannoma; Melanoma; Spermocytoma; Teratoma; Osteosarcoma; Xeroderma pitmentosum; Keratoacanthoma; Follicular carcinoma of thyroid; Ka Boxishi (Kaposi's) sarcoma, chronic lymphocytic leukemia, mantle cell lymphoma, large B cell lymphoid tumor.
" significant quantity in the treatment " is to be intended to show when salt of the present invention has needs individual, is enough to reach by the active mitigate the disease that suppresses the cyclin dependant kinase amount of result for the treatment of.Have in treatment effect specific compound of the present invention amount can along with such as the state of an illness and severity thereof, factors such as needing individual state own arranged and change, the technician that this amount generally has technical ability thus in the technology determines routinely.
It is selected that " at least a pharmaceutically acceptable vehicle, thinner, carrier or vehicle " can be easily generally has the technician of technical ability thus in the technology, and determined by required administering mode.The illustrative embodiment of suitable administering mode comprises per os, intranasal, non-through intestines, part, through skin, and per rectum.Pharmaceutical composition of the present invention can be to be familiar with this operator and to think suitable any medicament forms.The appropriate drug form comprises the preparation of solid, semisolid, liquid or freeze-drying, as tablet, powder agent, capsule, suppository, suspensoid, liposome and sprays.
To specific implementations of the present invention be described with reference the following example now.Should be appreciated that and disclose these embodiment only for the present invention being described and should limiting the scope of the invention by any way.
Embodiment 1 preparation compd A 1 (being formula (III) compound)
Prepare compd A 1 according to following synthetic schemes
(being formula (III) compound, 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid amides).
Synthetic schemes
The details of each step is provided in the following step 1.1 to 1.4.Step 1.5 is purification steps of choosing wantonly.
1.1
5-bromo-2-chloro-N-cyclopentyl pyrimidine-4-amine (A1f):
With the 5-bromo-2 of 250g (1.097mol, 140.4mL, 1.0 equivalents), the ethyl acetate of 4-dichloro pyrimidine (A1h) and 1127g (1250mL) be fed to 5L in nitrogen purging and the 4-neck round-bottomed flask that suitably is equipped with.Under 20 ℃ of temperature, stir this content and add the N of 283.5g (2.194mol, 382.0mL, 2.0 equivalents), the N-diisopropylethylamine.Add 102.8g (1.207mol, 119mL, 1.1 equivalents) the cyclopentamine solution that is dissolved in 1127g (1250mL) ethyl acetate in 60 minutes.Observe from 18 ℃ to 36 ℃ exothermic phenomenon.This solution is heated to 40 ℃.Keep this temperature to reach 6 hours at least or until confirming that with the HPLC analytical method all initial substances (A1h) are when all exhausting.The gained slurries are cooled to 25 ℃ and add the water of 500g (500mL), stirred this content 15 minutes, and allow and be separated.Remove bottom (water-based) and use 500g (500mL) water to wash organic layer again.Stir this sample and reach 15 minutes, and allow and be separated.Remove bottom (water-based).Making this organic phase be concentrated into (normal atmosphere) volume is 1500mL (batch temperature=82 ℃).Add 684g (1L) heptane and be 1500mL (batch temperature=85 ℃) with its reconcentration to volume.Again, add 684g (1L) heptane and be 1500mL (batch temperature=96 ℃) with its reconcentration to volume.Make this sample be cooled to 50 ℃ and add crystal seed.Continue to be cooled to 4 ℃ and this temperature is remained on 4 ℃ reach 1 hour.With solid filtering and use the cold heptane of 137g (200mL) (4 ℃) flush cake once.Dry these solids reach 16 hours under 50 ℃ of temperature, so that the compd A 1f of 259.0g (calibrated 88.0%) crystalline solid that is white in color shape, mp=95-96 ℃ to be provided.
1.2
3-[2-chloro-4-(cyclopentyl amino) pyrimidine-5-yl] third-2-alkynes-1-base-alcohol (A1d)
With the tetrahydrofuran (THF) of 5-bromo-2-chloro-N-cyclopentyl pyrimidine-4-amine (A1f) of 200g (0.723mol, 1.0 equivalents) and 2303g (2600mL) be fed to 5L in the 4-neck round-bottomed flask that nitrogen purges, suitably is equipped with.Stir this mixture, be heated to backflow (67 ℃), and collect the 200mL fraction.Make this sample be cooled to 25 ℃, and propargyl alcohol (A1e), the 570.3g (1.808mol of interpolation 52.7g (0.940mol, 55.6mL, 1.3 equivalents), 2.5 two (triphenylphosphine) palladium chlorides of three hydration tetrabutyl ammonium fluorides equivalent) and 25.4g (0.036mL, 0.05 equivalent).Stir this sample and be heated to backflow (67 ℃) and under this temperature, keep reaching 2 hours or in the initial substance (A1f) of confirming residue 5 to 7% with the HPLC analytical method.This sample is cooled to 25 ℃ and to be concentrated into volume in decompression under (100mbar, 30 ℃ of maximum internal temperature) be 1150mL, to remove tetrahydrofuran (THF).The ethyl acetate of charging 541g (600mL).Making this sample be concentrated into volume again under decompression (100mbar, 30 ℃ of maximum internal temperature) is 1150mL, to remove residual tetrahydrofuran (THF).Add the ethyl acetate of 2706g (3000mL) and be dissolved in the 63g Sodium Hydrogen Carbonate solution of 1500g (1500mL) water.This sample of stirring reaches 10 minutes and allows and is separated under 25 ℃ of temperature.Use 1500g (1500mL) water with organic phase (top) flushing once.Stirring this sample reaches 10 minutes and allows and be separated.Making this organic phase (top) be concentrated into volume under decompression (100mbar, 30 ℃ of the highest internal temperatures) is 625mL, to remove ethyl acetate.The acetone of 1582g (2000mL) is added in this enriched material.Stir this sample, be heated to backflow (58 ℃) and under this temperature, kept 30 minutes.Make it be cooled to 40 ℃ and through filter clarified with the diatomite filtration pad then.Twice of this flask of acetone rinsing of use 158g (200mL, 2x wash 100mL at every turn) and filter cake.Making this sample concentration to volume under decompression (100mbar, 30 ℃ of maximum internal temperature) is 460mL.Make it be cooled to 4 ℃ and under this temperature, kept 1 hour then.With solid filtering and use 158g (twice of 2 * 100mL) ice-cold acetone (4 ℃) flush cake.Dry this solid reaches 16 hours under 50 ℃ of temperature, is the compd A 1d of pale brown look crystalline solid shape, mp=162-163 ℃ so that 85.6g (calibrated 47.4%) to be provided.
(1.3 2-chloro-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-6-yl) methyl alcohol (A1c)
With 100g (purity: 98%, 0.389mol, 1.0 equivalents) the free tetrahydrofuran (THF) of peroxidation of 3-(2-chloro-4-(cyclopentyl amino) pyrimidine-5-yl) third-2-alkynes-1-alcohol (A1d), 880g (1000mL) and the tetrabutyl ammonium fluoride (1.0M THF solution) of 753g (856mL) is fed to the dry of 5L and in the 4-neck round-bottomed flask that nitrogen purges.Under 25 ℃ of temperature, stir this content and reach 10 minutes, and solution is heated to 60 ℃ then.Keep this temperature to reach 1.5 hours until confirming initial substance (A1d)≤2.5 ± 0.5% with the HPLC analytical method.Gained solution is cooled to is lower than 30 ± 3 ℃, and under reduced pressure distill to remove THF.Add 79g (100mL) 2-propyl alcohol.Stir this sample and reach 15 minutes, and in 30 minutes, slowly add 1000g (1000mL) water then.This sample of stirring reaches 30 minutes and filters then under 20 ± 3 ℃ of temperature.Use 200g (twice of 2 * 100mL) water flush cake.Drying solid reaches 16 hours under 50 ℃ of temperature, so that the compd A 1c of pale brown look, crystalline solid shape, mp=174-176 ℃ to be provided.
1.42-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid amides
(A1)
With 97.3g sodium cyanide, 2,500g (2-chloro-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-6-yl) methyl alcohol (A1c), 16,680g (19.5L) dimethylamine, A1a (2.0M THF solution) and 28, the anhydrous N of 320g (30.0L), dinethylformamide be fed to drying, in the ACE-100L reactor that nitrogen purges.Under 20 ± 3 ℃ of temperature, stir this mixture and reach 15 minutes.Add the Manganse Dioxide (IV) of 2.06kg then.Dark slurries were stirred 30 minutes and add every three parts of 30 minutes branches (first part: 2.06kg of the Manganse Dioxide (IV) of 12.36kg; Second part: 4.12kg; And the 3rd part: 6.18kg).After adding last portion, keep this sample to reach 1 hour and add the Manganse Dioxide (IV) of 6.18kg then.Keep this sample to reach 1 hour.Extract this reaction mixture sample then.If confirm initial substance (A1c)≤1.0 ± 0.5% with the HPLC analytical method, think that then this reacts completely.Then this reaction mixture warp is filtered to remove Manganse Dioxide (IV) with Celite pad.Use this reactor of ethyl acetate rinsing and the filter cake of 23L then._ 45 ± 3 ℃ of decompressions, under the 20mbar filtrate and fraction are merged to remove THF, dimethylamine and ethyl acetate.Decompression (70 ± 5 ℃ 5mbar) are further distilled this sample down to remove DMF.Use the ethyl acetate of 35L to dilute this enriched material.Use ferrous sulfate aqueous solution (in the water of 14L, to contain 1kg FeSO
47H
2O), the water of 15L and the last dark solution that uses the 10%NaCl aqueous solution flushing gained of 15L.Each flushing relief is separated.(45 ℃, 50mbar) organic phase removes water in the azeotropic mode in distillation.The rough A1 of gained (the dark sticky semi-solid residue of 2,788g) can be directly used in step subsequently.
1.5
Step: from rough A1, separate pure A1:
Can optionally come purifying from the rough A1 of step 1.4 by following method 1 or 2.
Method-1:
The rough A1 of 10g and 9mL1-propyl alcohol are leniently heated until obtaining the homogeneous dark solution.This solution is cooled to 25 ± 3 ℃ and slowly add 30 to 40mL hexanes.Sample is added crystal seed also to be stirred until observing crystallization.Add 50 to 60mL hexanes in addition lentamente.The about 90mL of hexane cumulative volume that adds.Under 22 ± 3 ℃ of temperature, keep these slurries to reach 2 hours, make it be cooled to 4 ℃ and kept in addition 2 hours then.With solid filtering.Use hexane flushing flask and filter cake as required.Dry this filter cake under 50 ℃ of temperature and 50mbar pressure is to provide the purifying A1 of 6.35g light brown yellow crystalline solid shape.The rate of recovery: 63.5%.
Method 2:
Preparation is dissolved in the solution of the rough A1 of 10g of 10mL EtOAc, and it is loaded on the 100g silica gel bed.Use 300mL EtOAc/ hexane (2/8) this tubing string of wash-out and abandon elutriant.Use 800mL EtOAc/ hexane (5/5) this tubing string of wash-out then and collect elutriant (#2) so that separated product.(#2) is concentrated into the thin oil shape with elutriant.Slowly add the 100mL hexane and under 22 ± 3 ℃ of temperature stirred sample reach 2 hours.This sample is cooled to 4 ℃ and extra the maintenance 2 hours.With solid filtering.Use hexane flushing flask and filter cake as required.Dry this filter cake under 50 ℃ of temperature and 50mbar pressure is to provide the purifying A1 of 6.05g light brown yellow crystalline solid shape.The rate of recovery is 60.5%.
Embodiment 2Preparation compd A 2 (being formula (IV) compound, 4-(6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester)
Prepare compd A 2 according to following synthetic schemes
(being formula (IV) compound, 4-(6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester).
Synthetic schemes
The details of each step is provided in the following step 2.1 to 2.4.
2.1
Hydrochloric acid 1-(6-nitropyridine-3-yl) piperazine
(14, propyl carbinol 000mL) is fed to the 4-neck round-bottomed flask that purges, suitably is equipped with through nitrogen of 22L with the piperazine (A2c) of the 5-chloro-2-nitropyridine (A2d) of 1392g (8.78mol, 1.0 equivalents), 1512g (17.56mol, 2.0 equivalents) and 11,340g.Stir gained suspension and be heated to 95 ℃.Keep this temperature to reach at least 24 hours or until confirm residue initial substance A2d 〉=2% (area standardization) with the HPLC analytical method.With the gained slurries at 1 hour internal cooling to 25 ℃.The solid warp is filtered with the polypropylene filter bed.Use total amount to be 2267g (twice of 2 * 1300mL) isopropyl acetate flush cake.Dry this solid reaches 16 hours under 60 ℃ of temperature, to provide 1769g (82.3%), not calibrated yellow crystal solid state and mp〉230 ℃ A2b.
(2.24-6-nitropyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester (A2a)
With 1-(6-nitropyridine-3-yl) piperazine hydrochloride (A2b) of 589g (2.41mol, 1.0 equivalents) be fed to 22L in the 4-neck round-bottomed flask that nitrogen purges, suitably is equipped with.Preparation be dissolved in 10,223g (11, the 500mL) solution of the 630.5g of tetrahydrofuran (THF) (2.89mol, 1.2 equivalents) two carbonic acid, two-tert-butyl ester, and it is fed in this flask.Stir gained suspension and make it be cooled to 8 ± 3 ℃.With the salt of wormwood of 499g (3.61mol, 1.5 equivalents) be fed to 5L in the 4-neck round-bottomed flask that nitrogen purges, suitably is equipped with.(3,600mL) water is added in this 5L flask with 3,600g.Stir the back and obtain solution.Make this solution be cooled to 25 ± 3 ℃ and in 30 minutes, it is moved in the reaction mixture.In whole interpolation process, batch temperature remains on≤and 12 ± 3 ℃.With this mixture heating up to 22 ± 3 ℃, and under this temperature, kept 1 hour in addition or until confirming no longer to manifest initial substance A2b with the TLC analytical method.This 2-phase mixture filters through the diatomite filter bed with 250g.Use total amount to be 800g (twice of 2 * 450mL) tetrahydrofuran (THF) flush cake.Make the merging of this flushing thing and filtrate.Allow and be separated and abandon water (bottom).Under decompression (100mbar, 40 ℃ of inner maximum temperatures), make filtrate be condensed into sticky mashed prod.
This complete procedure is repeated twice again.Be incorporated in 22L through the 4-neck circle flask that nitrogen purges and suitably is equipped with from the enriched material of all three-wheel gained.(6, heptane 900mL) is added in these concentrated batch of materials with 4,719g.Stir this sample and under decompression (100mbar, 40 ℃ of inner maximum temperatures), make it be condensed into sticky mashed prod.In addition, (4, heptane 600mL) is added in this concentrated batch of material with 3,146g.Under 37 ± 3 ℃ of temperature, stir gained suspension and reach 1 hour; Make it be cooled to 22 ± 3 ℃ and kept 15 minutes.The solid warp is filtered with the polypropylene filter bed, and (2 * 450mL) heptane is with twice of its flushing to use 615g.Under 55 ℃ of temperature, utilize nitrogen cleaning that this solid drying is reached 16 hours, with the compd A 2a of yellow that 2,088g (93.8%) is provided, crystalline solid shape and mp=173-174 ℃.
(2.34-6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester (A2)
Heavy wall Pa Er (Parr) bottle that 4-(6-nitropyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester (A2a) of 68g (0.22mol), methanol feeding that 6.8g10% carbon carries palladium, 50% moisture moist catalysis and 807g (1020mL) are purged through nitrogen to 2.5L.Use nitrogen (about 30psi) with reactor inerting three times, so that loose air above the reaction mixture of row during each inerting.Utilize hydrogen (ca.30psi) this container twice that pressurizes, so that the loose air of reaction mixture top of row when pressurizeing at every turn.Utilize hydrogen that this reactor is forced into 45psi.Start the vibrator electric motor.This reaction is thermopositive reaction.Temperature can be in 15 minutes rises to 54 ℃ from 19 ℃, and the absorption of hydrogen can stop during this period.Allow mixture at 1 hour internal cooling to 30 ℃, stop vibrator this moment.Use nitrogen as indicated above (inerting reactor) displacement to fall hydrogen.By filtering to remove catalyzer by 10g diatomite filtration pad.This complete procedure is repeated once again, the filtrate of twice gained is merged and be fed in the clean 3L4-neck round-bottomed flask.
2.4 product separates
Stirring is derived from the filtrate of step 2.3 and makes it be condensed into the mashed prod of thickness under decompression (50mbar, 40 ℃ of maximum internal temperature).The t-butyl methyl ether of 190g (250mL) is fed in the resistates.Stir this sample again and under decompression (50mbar, 30 ℃ of maximum internal temperature), make it be condensed into the mashed prod of thickness.Be fed to the heptane of 342g (500mL) in the resistates and under 22 ± 3 ℃ of temperature, stir gained suspension and reach 15 minutes.Heptane flush cake with solid filtering and use 68g (100mL).Dry this solid reaches 16 hours under 50 ℃ of temperature, so that the compd A 2 of the pale brown colour disk shape of 112.3g (93.4%) and mp=124-126 ℃ to be provided.
Prepare compd A 4 according to following synthetic schemes
(being formula (I) compound, 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide).
Synthetic schemes:
The details of each step is provided in the following step 3.1 to 3.2.
3.14-(6-(7-cyclopentyl-6-(dimethylamino formyl radical)-7H-pyrrolo-[2,3-d] pyrimidine-2-base
Amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (A3)
With 43.9g (0.15mol, 1.0 2-chloro-7-cyclopentyl-N equivalent), N-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid amides (being derived from the rough A1 of above step 1.4), 45.9g (0.165mL, 1.1 4-equivalent) (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester (A2), 0.67g (3.0mmol, 0.02 acid chloride (II) equivalent), 3.73g (6.0mmol, 0.04 (±) 2 equivalent), two (diphenylphosphino)-1 of 2'-, the 1'-naphthyl naphthalene, ± BINAP (2, two (diphenylphosphino)-1 of 2'-, 1'-naphthyl naphthalene) and the 4-methyl-2 pentanone of 275g (344mL) be fed to 3L in ARGO (Argonaut) reactor assembly that nitrogen purges.Stir gained suspension and be heated to 40 ± 3 ℃.The cesium carbonate that in 15 minutes, adds 73.3g (0.225mol, 1.5 equivalents) with 5 to 10 parts of components.Stir gained suspension and be heated to 100 ± 3 ℃.Keep this temperature to reach 3 hours or until confirm residue initial substance A1≤2% (area standardization) with the HPLC analytical method.Use processing to handle control and check reaction process.Make sample be cooled to 70 ± 3 ℃ and in 5 minutes, add 344g (344mL) water.Make sample be cooled to 50 ± 3 ℃ and under this temperature, kept 30 minutes.In 30 minutes, add the heptane of 353g (516mL), and stir this sample and reach 2 hours.Make this mixture be cooled to 22 ± 3 ℃ and keep at least 4 hours (holding point) then.Solid is through filtering with the polypropylene filter bed.Use the 4-methyl-2 pentanone of 24g (30mL) and ice-cold mixture (4 ℃) flush cake of 41g (60mL) heptane.Dry these solids show organic solvent≤1% until HSGC PSC under 60 ℃ of temperature, so that the A3 of the pale brown look of 72.6g, solid state, mp=215-217 ℃ to be provided.
3.27-cyclopentyl-N, N-dimethyl-2-(5-(piperazine-1-yl) pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid amides (A4):
With 67.4g (0.126mol; 1.0 (toluene feed of 6-(7-cyclopentyl-6-(dimethylamino formyl radical)-7H-pyrrolo-[2,3-d] pyrimidine-2--amino pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (A3) and 329g (380mL) is to the ARGO reactor assembly through the nitrogen purging of 3L for 4-equivalent).Stirred suspension and make it be cooled to 12 ± 3 ℃.In 30 minutes, add the 6N aqueous hydrochloric acid of 138g (126mL, 6.0 equivalents), keep batch temperature≤15 ± 3 ℃.The 2-phase solution of gained is heated to 25 ± 3 ℃, and under this temperature, keeps reaching 30 minutes or until confirm residue initial substance A3≤2% (area standardization) with the HPLC analytical method.Utilize processing to handle control and check reaction process.Add the 1N aqueous hydrochloric acid of 250g (250mL) and mixture was stirred 5 minutes.2-phase reaction mixture is through filtering with 25g diatomite filter bed.Allow and be separated.The 4-neck round bottom that water (containing product) is fed to 2L burns (as according to device portal 4 described outfits) and makes it be cooled to 15 ± 3 ℃.Slowly add 50% aqueous sodium hydroxide solution of 62g (41mL), the pH value be adjusted to 3.2 ± 0.3, in whole interpolation process, make batch temperature remain on≤27 ± 3 ℃.Add 16.4g silicon-thiol-functional silica gel.Under 50 ± 3 ℃ of temperature, stir slurries and reach 3 hours.Leach resin, use 50mL water rinse flask and filter cake.Rinsing thing and filtrate are merged.This filtrate is transferred back in the flask, and adds 16.4g silicon-thiol-functional silica gel.Under 50 ± 3 ℃ of temperature, stir slurries and reach 3 hours.Leach silica gel.Use 50mL this flask of water rinse and filter cake.Rinsing thing and filtrate are merged.This filtrate is transferred back in the flask, and adds 16.4g silicon-thiol-functional silica gel again.Under 50 ± 3 ℃ of temperature, stir slurries and reach 3 hours.Leach silica gel.Use 50mL this flask of water rinse and filter cake.Make the merging of rinsing thing and filtrate.This filtrate is fed to the ARGO reactor assembly through washing of 3L and makes it be cooled to 15 ± 3 ℃.Slowly add 50% aqueous sodium hydroxide solution of 17g (18mL), the pH value is adjusted to 12.5 ± 0.5, so that product (batch volume=900mL, maximum volume) precipitation.Under 22 ± 3 ℃ of temperature, stir this sample and reach at least 6 hours.The solid warp is filtered with the polypropylene filter bed.Use 340g (four pH value≤9 until the flushing thing of 4 * 85mL) water flush cake.Dry these solids reach at least 16 hours or until LOD≤1% under 60 ℃ of temperature, are the compd A 4 of pale brown look solid state, mp=194-195 ℃ so that 45.7g (84.9%, calibrated) to be provided.
Embodiment 4The succinate of preparation 7-cyclopentyl-2-(5-piperazine-1-yl pyridines-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid diformamide
Prepare compd A 6 according to following synthetic schemes
(be formula (II) compound, 7-cyclopentyl-N, N-dimethyl-2-(5-(piperazine-1-yl pyridines-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid amides succinate).
With the 2-propyl alcohol of the succsinic acid (A5) of 11.16g (0.0945mol, 1.05 equivalents) and 245g (312mL) be fed to 1L in the 4-neck round-bottomed flask that nitrogen purges.Stirred suspension and be heated to 65 ± 3 ℃ is to obtain clear solution.This solution filters through glass fiber filter paper when warm.Filtrate is remained on 30 ± 3 ℃, be used for being added into A4.With 39.11g (0.09mol, 1.0 7-cyclopentyl-N equivalent), N-dimethyl-2-(5-(piperazine-1-yl pyridines-2-base amino-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid amides (A4) and 1115g (1420mL) 2-propyl alcohol be fed to 2L in the 4-neck round-bottomed flask that nitrogen purges.Stir gained suspension and be heated to 80 ± 3 ℃, obtain muddy yellow solution.This solution is cooled to 70 ± 3 ℃ and filter through the 25g Celite pad.With this warm, filtered A4 solution be transferred to 3L in the ARGO reactor assembly that nitrogen purges, and reheat to 80 ± 3 ℃.Added succsinic acid/2-propanol solution in 1 hour, whole interpolation process keeps 80 ± 3 ℃.After adding 80% succinic acid solution, in batch of material, add crystal seed.After this interpolation was finished, this sample stirred 1 hour and 1 hour internal cooling to 20 ± 3 ℃, kept 30 minutes at 80 ± 3 ℃, and with solid filtering.Use the 2-propyl alcohol filter wash cake of 78g (100mL).This solid provides 47.16g (94.9%, calibrated) compd A 6 60 ℃ of dryings at least 16 hours or until LOD≤1%, is the yellow crystal solid, mp=202-203 ℃.
Under 90%RH, gained compd A 6 can change into hydrate forms from the non-hydrate form among about 7.35% the embodiment 4.
To be exposed in the humidity circulation of 0-80-0%RH at embodiment 4 gained compd As 6, when can not betide 80%RH with form transformation observed under the affirmation 90%RH.Table 2 and Fig. 5 show that compd A 6 absorbs and reach 0.5% moisture that this reflects that it does not almost have the moisture absorption behavior under 80%RH under 80%RH.Fig. 5 and 6 shows that formula (II) compound that is reflected as the non-hydrate form is exposed to the stability that is up to the physical aspect among the 80%RH.Because the stability of former spice and the physical aspect of medicine under 75%RH is gratifying, so formula (II) compound (non-hydrate) is suitable for developing.
Under 80%RH, only about 0.52% embodiment 4 gained compd As 6 can change into hydrate forms from the non-hydrate form.
Embodiment 7 solubleness:
The solubleness of non-hydrate form in water is 30mg/mL.On the contrary, the solubleness of hydrate forms is lower and be to be lower than 0.5mg/mL significantly.
The thermoisopleth table of table 1 formula (II) compound (0-90-0%RH circulation)
The thermoisopleth table of table 2 formula (II) compound (0-80-0%RH circulation)
Claims (18)
1. the succinate of a 7-cyclopentyl-2-(5-piperazine-1-base-pyridine-2-base is amino)-7H-pyrrolo-[2,3-d] pyrimidine-6-carboxylic acid dimethylformamide.
2. salt as claimed in claim 1, wherein this salt has formula (II)
3. salt as claimed in claim 1, it is non-hydrate forms.
4. salt as claimed in claim 1, it is hydrate forms.
5. pharmaceutical composition, it comprises:
(a) in the treatment significant quantity as each salt in the claim 1 to 4; And
(b) at least a pharmaceutically acceptable vehicle, thinner, carrier or vehicle.
6. treat cell cycle and regulate the method that the inhibition of protein dependent kinase activity has the disease of reaction for one kind, this method comprises the step as each salt in the claim 1 to 4 for the treatment of significant quantity to the individuality of this treatment of need.
7. the method for a preparation formula (I) compound, it comprises:
(1) makes
With
Reaction is to form
(2) make
Change into
8. method as claimed in claim 7, wherein step (1) is at Pd (OAc)
2, BINAP and Cs
2CO
3Existence under carry out.
9. method as claimed in claim 7, wherein step (2) is to carry out in the presence of HCl (aqueous solution) and toluene.
10. method as claimed in claim 7 wherein makes
Further change into
11. as the method for claim 10, wherein this conversion is to reach at IPA
Existence under carry out.
12. the method for a preparation formula (III) compound:
It comprises conversion
13. as the method for claim 12, wherein
Conversion be at MnO
2, NaCN,
And carry out under the existence of THF.
14. as the method for claim 12, wherein
Be certainly
Form.
15. the method for a preparation formula (III) compound,
It comprises:
(1) makes
With
Reaction is to form
(2) make
Conversion is to form
(3) make
Conversion is to form
And (4) make
Conversion is to form
16. the method for a preparation formula (IV) compound:
It comprises:
(1) makes
With
Reaction is to form
(2) make
Conversion is to form
And (3) make
Conversion is to form
17. as the method for claim 16, wherein this is reflected under the existence of positive BuOH and carries out.
18. the method for a preparation formula (IV) compound:
It comprises:
(1) makes
With
Reaction is to form
And (2) further make
Conversion is to form
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| CN201510746374.2A CN105399743A (en) | 2010-11-10 | 2011-11-09 | Salt(s) Of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic Acid Dimethylamide And Processes Of Making Thereof |
| CN202110832802.9A CN113956257A (en) | 2010-11-10 | 2011-11-09 | Salt of cell cycle regulatory protein dependent kinase inhibitor and preparation method thereof |
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| CN201510746374.2A Division CN105399743A (en) | 2010-11-10 | 2011-11-09 | Salt(s) Of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic Acid Dimethylamide And Processes Of Making Thereof |
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| CN110156793B (en) * | 2018-07-13 | 2022-01-14 | 安礼特（上海）医药科技有限公司 | Novel crystal form of Ribociclib monosuccinate and preparation method thereof |
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| CN112010857B (en) * | 2019-05-30 | 2021-11-05 | 常州制药厂有限公司 | Crystal form of ribociclib succinate |
| CN112010857A (en) * | 2019-05-30 | 2020-12-01 | 常州制药厂有限公司 | Crystal form of ribociclib succinate |
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